What are the next steps for a patient with a positive viral load after treatment with Epclusa (Sofosbuvir/Velpatasvir) for hepatitis C?

Management of Persistent HCV Viremia After Epclusa Treatment

For a patient with detectable HCV RNA after completing Epclusa (sofosbuvir/velpatasvir) therapy, the immediate priority is to determine whether this represents on-treatment virologic failure, relapse, or reinfection, followed by resistance testing and selection of an alternative DAA regimen with a different mechanism of action.

Initial Assessment and Timing Clarification

The first critical step is establishing when the positive viral load was detected relative to treatment completion:

• If HCV RNA is detectable at week 4 of treatment: Repeat quantitative HCV RNA testing at week 6 is recommended. If viral load has increased by >10-fold (>1 log10 IU/mL), discontinuation of therapy should be considered 1
• If HCV RNA is positive at end of treatment (week 12): This represents on-treatment virologic failure 1
• If HCV RNA is positive at 12 weeks post-treatment (SVR12 timepoint): This represents virologic relapse 1, 2
• If HCV RNA was negative at SVR12 but subsequently became positive: Consider reinfection versus late relapse 2

Essential Diagnostic Workup

Before initiating retreatment, obtain the following:

• Resistance-associated substitution (RAS) testing: Sequence NS5A and NS5B regions to identify mutations that may have emerged during Epclusa therapy 3, 4
• HCV genotype and subtype confirmation: Verify the original genotype, as this guides salvage therapy selection 5
• Quantitative HCV viral load: Establish baseline viremia for retreatment 5
• Complete blood count, hepatic function panel, INR, and calculated GFR: Assess current liver function and synthetic capacity 5
• Fibrosis assessment: Determine if cirrhosis is present via FibroScan, FibroTest, or imaging, as this impacts treatment duration and regimen selection 6, 4

Retreatment Strategy

For Treatment-Experienced Patients Without Cirrhosis

The preferred salvage regimen is sofosbuvir/velpatasvir/voxilaprevir (Vosevi) for 12 weeks, which adds a protease inhibitor (voxilaprevir) to overcome NS5A resistance 3. This triple-drug combination targets three different viral proteins simultaneously, reducing the likelihood of resistance.

For Treatment-Experienced Patients With Compensated Cirrhosis

• Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks remains the preferred option 3
• Consider adding weight-based ribavirin (1000-1200 mg daily based on body weight) if NS5A RASs are present, particularly the Y93H mutation in genotype 3 3
• Treatment duration may be extended to 24 weeks in patients with multiple prior treatment failures and documented RASs 3

For Patients With Decompensated Cirrhosis (Child-Pugh B or C)

Referral to a hepatologist or liver transplant center is mandatory 1. These patients require:

• Careful assessment of Child-Pugh score, as patients with Child-Pugh C have significantly lower SVR rates (50% vs 96% for Child-Pugh B) 4
• Consideration of liver transplantation evaluation if MELD score is elevated 1
• Close monitoring during retreatment for hepatic decompensation events 4

Genotype-Specific Considerations

Genotype 3 Patients

Genotype 3 is particularly challenging after Epclusa failure:

• NS5A RASs (especially Y93H) are common and significantly reduce retreatment success rates 3, 4
• If sofosbuvir/velpatasvir/voxilaprevir fails, consider glecaprevir/pibrentasvir + sofosbuvir + ribavirin for 24 weeks as a rescue regimen 3
• This four-drug combination has achieved SVR in multiply-relapsed genotype 3 patients with documented NS5A resistance 3

Genotype 1b Patients

• Patients with baseline NS5A RASs have lower SVR rates (43% vs 100% without RASs) 4
• Sofosbuvir/velpatasvir/voxilaprevir remains highly effective even with NS5A resistance 3

Monitoring During Retreatment

• HCV RNA at weeks 2,4, and 12 (or 24) to assess adherence and early virologic response 1
• Complete blood count, hepatic function panel, and creatinine at week 4 and as clinically indicated 1
• More frequent monitoring if ribavirin is added: Check hemoglobin every 2-4 weeks due to hemolytic anemia risk 1

Critical Pitfalls to Avoid

1. Do not retreat with the same regimen (sofosbuvir/velpatasvir) that failed 1. This will almost certainly fail again due to established resistance.

2. Do not use sofosbuvir/daclatasvir as salvage therapy after Epclusa failure, as cross-resistance between velpatasvir and daclatasvir (both NS5A inhibitors) is common 3

3. Do not delay resistance testing. RAS testing should be performed before retreatment to guide regimen selection 3

4. Ensure strict adherence counseling. Verify that the initial treatment failure was not due to non-adherence, as this would not require a different regimen 1

5. Screen for drug-drug interactions before retreatment, particularly with proton pump inhibitors, which can reduce velpatasvir absorption 1

Post-Retreatment Surveillance

After achieving SVR with salvage therapy:

• Confirm SVR12 with quantitative HCV RNA 2
• If cirrhosis is present: Lifelong HCC surveillance with ultrasound every 6 months and endoscopic variceal screening every 2-3 years 1, 2, 5
• If ongoing risk factors exist (injection drug use, high-risk sexual behavior): Annual HCV RNA testing to detect reinfection 2
• If no cirrhosis and no ongoing risk factors: No further HCV-specific monitoring is needed after confirming SVR 2